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Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response.Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response.Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/μl; P = 0.027), higher HIV viral load (HR = 2.22 per log 10 copies/ml; P = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10 copies/ml; P = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score70 (HR = 9.17; P = 0.045), abnormal chest X-ray (HR = 8.41; P = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10 copies/ml; P 0.001).Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Burkitt lymphoma (BL) accounts for the majority of pediatric non-Hodgkin lymphomas (NHL) and is relatively rare but significantly more lethal when diagnosed in adults. The global incidence is highest in Sub-Saharan Africa, where Epstein-Barr virus (EBV) positivity is observed in 95% of all tumors. Both pediatric (pBL) and adult (aBL) cases are known to share some driver mutations, for example MYC translocations, which are seen in > 90% of cases. Sequencing efforts have identified many common somatic alterations that cooperate with MYC in lymphomagenesis with approximately 30 significantly mutated genes (SMG) reported thus far. Recent analyses revealed non-coding mutation patterns in pBL that were attributed to aberrant somatic hypermutation (aSHM). We sought to identify genomic and molecular features that may explain clinical disparities within and between aBL and pBL in an effort to delineate BL subtypes that may allow for the stratification of patients with shared pathobiology. Through comprehensive sequencing of BL genomes, we found additional SMGs, including more genetic features that associate with tumor EBV status, and established three new genetic subgroups that span pBL and aBL. Direct comparisons between pBL and aBL revealed only marginal differences and the mutational profiles were consistently better explained by EBV status. Using an unsupervised clustering approach to identify subgroupings within BL and diffuse large B-cell lymphoma (DLBCL), we have defined three genetic subgroups that predominantly comprise BL tumors. Akin to the recently defined DLBCL subgroups, each BL subgroup is characterized by combinations of common driver mutations and non-coding mutations caused by aSHM. Two of these subgroups and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among the aBL and pBL cohorts. These findings highlight not only a shared pathogenesis between aBL and pBL, but also establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological studies, and diagnostic and therapeutic strategies.

Introduction: Burkitt lymphoma (BL) accounts for approximately 50% of all pediatric non-Hodgkin lymphomas compared to 1-2% in adults. Adult BL (aBL) remains a poorly understood entity and its relationship to pediatric BL (pBL) and to DLBCL has not been fully elucidated. The variable treatment outcomes between these entities necessitate a more thorough understanding of the genetic and molecular features underlying their biology to enable better prognostication and more effective treatments. We sought to comprehensively determine genetic features shared with DLBCL and those that are unique to BL, to further delineate genetic subgroupings within each entity. Methods: Samples for this study were collected through the Burkitt Lymphoma Genome Sequencing Project (BLGSP). We sequenced the tumor genomes of 139 pBL and 92 aBL, consisting of both EBV-positive (EBV+) and EBV-negative (EBV-) BLs, and compared these to the genomes of 252 DLBCL patients. All cases were analyzed for simple somatic mutations (SSM), recurrent copy number variations (CNV), structural variations (SV), aberrant somatic hypermutation (aSHM), and SSM hotspots. Mutations were used as features for the identification of genetic subgroups using non-negative matrix factorization (NMF) clustering. Results: Clustering of BL and DLBCL revealed six distinct genetic subgroups (Figure 1) with three primarily representing DLBCLs (DLBCL-1, DLBCL-2, and DLBCL-3) and three predominantly comprising BLs (M53-BL, IC-BL, and DGG-BL). The DLBCL-predominant subgroups partially overlapped with those previously described and resembled features of EZB and ST2-like subgroups. The frequency of aBLs within these subgroups was higher than that of pBL patients (p=0.0005). The new cluster M53-BL consists of both pBL (9/27) and aBL (13/27) samples and is characterized by the highest prevalence of mutations in TP53 accompanied by the paucity of other driver mutations but without the aneuploidy associated with the A53 subgroup described in DLBCL. Enrichment of EBV- samples in this cluster further corroborate our previous findings of TP53 mutations being associated with EBV- BL. IC-BL is characterized by mutations in ID3, CCND3, and SMARCA4. In contrast, DGG-BL, where 65% of the cluster consisted of EBV+ BL samples, had mutations in DDX3X, GNA13, and GNAI2. Using a linear model, we compared the rates of aSHM in BL genomes from all clusters and identified the DLBCL-3 cluster to harbor the highest aSHM rates at common sites while the M53-BL cluster harbored the lowest rates. To further establish the biological basis of unique clusters within BL, we conducted differential gene expression analyses between the two major BL genetic subgroups, DGG-BL and IC-BL. We identified a total of 86 differentially expressed genes between the two clusters (p.adj < 0.01 and |log2foldChange| > 1). Among the genes with the strongest differential expression were IRF4, SERPINA9, and TNFRSF13B. Each of these are notable as their expression is a component of the DLBCL cell-of-origin and double-hit signature classifiers. Further, we found IRF4 expression to be one of the strongest predictors of cluster membership, with high IRF4 expression associated with IC-BL membership. Using TP53 and ID3 mutations as a proxy for M53-BL and IC-BL clusters in aBL, we found mutations in TP53 to be associated with significantly inferior progression free survival (PFS) at 2 year follow up, while mutations in ID3 were associated with overall better PFS at 2 year follow up. Conclusion: This work identifies novel genetic subgroups within BL with characteristic genetic and gene expression differences and some bearing relationship to DLBCL subgroups. The three subgroups with predominantly BL samples (DGG-BL, IC-BL, and M53-BL) each comprised a mixture of aBL and pBL samples, confirming similar molecular features in these entities. The IC-BL cluster is associated with mutations in ID3 and CCND3, high IRF4 expression, and ID3 mutated cases exhibited significantly better outcomes. M53-BL is associated with TP53 mutations and inferior PFS in aBL, representing a subset of patients to be considered for novel treatment approaches. These findings highlight shared pathogenesis between aBL and pBL and establish genetic subtypes within BL that delineate cases with distinct molecular and clinical features. This provides a new framework for new diagnostic and therapeutic strategies. Figure 1 Figure 1. Disclosures Abramson: Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Casper: EUSA Pharma: Consultancy. Gerrie: Roche: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria. Grande: Sage Bionetworks: Current Employment. Mullighan: Illumina: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. Scott: NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. . Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties.